title: Progeroid laminopathy with restrictive dermopathy-like features caused by an isodisomic LMNA mutation p.R435C.
abstract: The clinical course of a female patient affected by a progeroid syndrome with Restrictive Dermopathy (RD)-like features was followed up. Besides missing hairiness, stagnating weight and growth, RD-like features including progressive skin swelling and solidification, acrocontractures, osteolysis and muscular hypotension were observed until the patient died at the age of 11 months. A homozygousLMNA mutation c.1303C>T (p.R435C) was found by Sanger sequencing. Haplotyping revealed a partial uniparental disomy of chromosome 1 (1q21.3 to 1q23.1) including the LMNA gene. In contrast to reported RD patients with LMNA mutations, LMNA p.R435C is not located at the cleavage site necessary for processing of prelamin A by ZMPSTE24 and leads to a distinct phenotype combining clinical features of Restrictive Dermopathy, Mandibuloacral Dysplasia and Hutchinson-Gilford Progeria. Functionally, LMNA p.R435C is associated with increasing DNA double strand breaks and decreased recruitment of P53 binding protein 1 (53BP1) to DNA-damage sites indicating delayed DNA repair. The follow-up of the complete clinical course in the patient combined with functional studies showed for the first time that a progressive loss of lamin A rather than abnormal accumulation of prelamin A species could be a pathophysiological mechanism in progeroid laminopathies, which leads to DNA repair deficiency accompanied by advancing tissue degeneration.
authors.affiliation: Department of Women and Child Health, Hospital for Children and Adolescents, Centre of Pediatric Research, University Hospital, University of Leipzig, Leipzig, Germany. Sven.Starke@medizin.uni‐leipzig.de
authors.forename: Sven
authors.initials: S
authors.lastname: Starke
authors.forename: Peter
authors.initials: P
authors.lastname: Meinke
authors.forename: Daria
authors.initials: D
authors.lastname: Camozzi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mattioli
authors.forename: Roland
authors.initials: R
authors.lastname: Pfaeffle
authors.forename: Manuela
authors.initials: M
authors.lastname: Siekmeyer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hirsch
authors.forename: Lars Christian
authors.initials: LC
authors.lastname: Horn
authors.forename: Uwe
authors.initials: U
authors.lastname: Paasch
authors.forename: Diana
authors.initials: D
authors.lastname: Mitter
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lattanzi
authors.forename: Manfred
authors.initials: M
authors.lastname: Wehnert
authors.forename: Wieland
authors.initials: W
authors.lastname: Kiess
mesh_terms: D003057:Cockayne Syndrome / Q000235:genetics* / Q000473:pathology*; D004260:DNA Repair; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007223:Infant; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010375:Pedigree; D012868:Skin Abnormalities / Q000235:genetics* / Q000473:pathology*
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A